Moving towards high-resolution descriptions of the molecular interactions and structural rearrangements of the human hepatitis B core protein.
The human hepatitis B virus core protein (HBc) forms icosahedral capsids and plays central roles in viral replication. The critical interactions that HBc makes prior to capsid formation (potential drug targets) have proved refractory to structural characterisation as HBc aggressively forms capsids. Our current structural understanding of HBc interactions is therefore capsid-centric, and this view has been limited by the resolution of cryo-electron microscopy and the inherent difficulties in getting high-quality crystals of viral capsids. To augment these approaches, we used capsid-dissociating conditions, solution NMR, and biophysical methodologies to directly characterise, at atomic resolution, the structural properties of dimeric HBc, as well as its dynamics and intermolecular interactions. Dimeric HBc recapitulates the structural properties and binding interactions of HBc within the context of capsids. Antiviral peptides induced long-range structural asymmetry in dimeric HBc, providing new insights into how ligand binding can effect communication between different regions of HBc and, therefore, between the capsid interior and the capsid exterior. Our work also paves the way for detailed descriptions of the previously invisible early stages of replication involving soluble HBc.
Freund
Stefan M V
SM
MRC Centre for Protein Engineering, Hills Road, Cambridge CB2 0QH, UK.
Johnson
Christopher M
CM
Jaulent
Agnes M
AM
Ferguson
Neil
N
D000998:Antiviral Agents / Q000378:metabolism; D002151:Calorimetry; D002213:Capsid / Q000737:chemistry / Q000378:metabolism; D019281:Dimerization; D006512:Hepatitis B Core Antigens / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D027701:Organic Cation Transport Proteins / Q000378:metabolism; D000075102:Organic Cation Transporter 2; D010455:Peptides / Q000378:metabolism; D011485:Protein Binding; D017433:Protein Structure, Secondary; D012996:Solutions
D000998:Antiviral Agents; D006512:Hepatitis B Core Antigens; D027701:Organic Cation Transport Proteins; D000075102:Organic Cation Transporter 2; D010455:Peptides; C491013:SLC22A2 protein, human; D012996:Solutions